Familial erythrophagocytic lymphohistiocytosis (FEL) is an autosomal recessive genetic disease usually fatal in childhood. Neither the direct etiology, the pathogenesis, nor a definitive marker of this pediatric disease has been identified. We have documented a consistent pattern of hyperlipidemia, cellular immunodeficiency, and plasma-mediated inhibition of immune responses in FEL. The amelioration of these abnormalities and the transient clinical remissions resulting after repeated plasmaphereses suggested that the immunodeficiency is secondary and possibly related to abnormal lipid metabolism in FEL. This is supported by our additional findings of elevated hepatic concentrations of the acidic glycosphingolipids, gangliosides, in FEL. Therefore, our present objective is to test the hypothesis that abnormal accumulation of gangliosides is an inherent characteristic and primary defect in FEL. We shall isolate, quantitate and qualitatively identify gangliosides from (1) liver and other pathologically affected tissues, including brain, (2) the large quantities of plasma stored following therapeutic plasmapheresis of FEL patients, and (3) smaller plasma samples from additional patients and obligate heterozygotes. The tissue and plasma samples required for this study are already available in an FEL tissue bank we have established. Gangliosides will be isolated from tissues by standard isolation methods. Ganglioside purification from plasma, previously technically difficult, will be accomplished using a simple new ganglioside isolation procedure which we have developed for this purpose. Quantitation, and qualitative analysis by two-dimensional thin-layer chromatography, will be used to compare gangliosides isolated from tissues of patients and normal and disease controls. Overall, these studies will delineate the specific ganglioside alterations in FEL. These results will provide the foundation for identification of the molecular basis for the pathogenesis of FEL and for the development of improved treatment and diagnosis of this disease.